tbuckley/cabot-search huggingface dataset:
A leap towards personalised therapy of acute lung injury
Authors: Martin Witzenrath, Tobias Welte
Journal: European Respiratory Journal (2022)

Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in December 2019 in Wuhan, China. Since then, it has spread globally, resulting in the ongoing COVID-19 pandemic, causing more than 580 million documented cases. While most of these cases are characterised by a mild course of disease, a considerable percentage of SARS-CoV-2 infections evoke severe lung involvement, and ultimately lead to acute respiratory distress syndrome (ARDS). The latter has been causative for most of the >6 million documented deaths between December 2019 and September 2022. Despite the availability of effective vaccines and antivirals, COVID-19 ARDS will thus keep on challenging healthcare workers around the globe. Adopting a personalised therapy for patients with acute respiratory distress syndrome (ARDS) may improve outcomes <https://bit.ly/3EqZupE>
Single-cell transcriptional profiling uncovers the association between EOMES+CD8+ T cells and acquired EGFR-TKI resistance
Authors: Guosheng Wang, Jiaxing Sun, Jing Zhang, Qiping Zhu, Jingjing Lu, Shaoyong Gao, Feilong Wang, Qi Yin, Yuan Wan, Qiang Li
Journal: Drug Resistance Updates (2022)
Mechanisms and treatments of neuropathic itch in a mouse model of lymphoma
Authors: Ouyang Chen, Qianru He, Qingjian Han, Kenta Furutani, Yun Gu, Madelynne Olexa, Ru-Rong Ji
Journal: Journal of Clinical Investigation (2022)

Our understanding of neuropathic itch is limited due to a lack of relevant animal models. Patients with cutaneous T cell lymphoma (CTCL) experience severe itching. Here, we characterize a mouse model of chronic itch with remarkable lymphoma growth, immune cell accumulation, and persistent pruritus. Intradermal CTCL inoculation produced time-dependent changes in nerve innervations in lymphoma-bearing skin. In the early phase (20 days), CTCL caused hyperinnervations in the epidermis. However, chronic itch was associated with loss of epidermal nerve fibers in the late phases (40 and 60 days). CTCL was also characterized by marked nerve innervations in mouse lymphoma. Blockade of C-fibers reduced pruritus at early and late phases, whereas blockade of A-fibers only suppressed late-phase itch. Intrathecal (i.t.) gabapentin injection reduced late-phase, but not early-phase, pruritus. IL-31 was upregulated in mouse lymphoma, whereas its receptor Il31ra was persistently upregulated in Trpv1-expressing sensory neurons in mice with CTCL. Intratumoral anti–IL-31 treatment effectively suppressed CTCL-induced scratching and alloknesis (mechanical itch). Finally, i.t. administration of a TLR4 antagonist attenuated pruritus in early and late phases and in both sexes. Collectively, we have established a mouse model of neuropathic and cancer itch with relevance to human disease. Our findings also suggest distinct mechanisms underlying acute, chronic, and neuropathic itch.
A Framework for Public Health Authorities to Evaluate Health Determinants for Wastewater-Based Epidemiology
Authors: Carla J. Eaton, Sarah Coxon, Isabelle Pattis, Andrew Chappell, Joanne Hewitt, Brent J. Gilpin
Journal: Environmental Health Perspectives (2022)

Background: Wastewater-based epidemiology (WBE) is rapidly developing as a powerful public health tool. It can provide information about a wide range of health determinants (HDs), including community exposure to environmental hazards, trends in consumption of licit and illicit substances, spread of infectious diseases, and general community health. As such, the list of possible candidate HDs for WBE is almost limitless. Consequently, a means to evaluate and prioritize suitable candidates for WBE is useful, particularly for public health authorities, who often face resource constraints. Objectives: We have developed a framework to assist public health authorities to decide what HDs may be appropriate for WBE and what biomarkers could be used. This commentary reflects the experience of the authors, who work at the interface of research and public health implementation. Discussion: To be suitable for WBE, a candidate HD should address a public health or scientific issue that would benefit from better understanding at the population level. For HDs where information on individual exposures or stratification by population subgroups is required, WBE is less suitable. Where other methodologies are already used to monitor the candidate HD, consideration must be given to whether WBE could provide better or complementary information to the current approach. An essential requirement of WBE is a biomarker specific for the candidate HD. A biomarker in this context refers to any human-excreted chemical or biological that could act as an indicator of consumption or exposure to an environmental hazard or of the human health state. Suitable biomarkers should meet several criteria outlined in this commentary, which requires background knowledge for both the biomarker and the HD. An evaluation tree summarizing key considerations for public health authorities when assessing the suitability of candidate HDs for WBE and an example evaluation are presented. https://doi.org/10.1289/EHP11115
A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway
Authors: Sae-Bom Yoon, Hyowon Hong, Hee-Jong Lim, Ji Hye Choi, Yoon Pyo Choi, Seong Wook Seo, Hyuk Woo Lee, Chong Hak Chae, Woo-Kyu Park, Hyun Young Kim, Daeyoung Jeong, Tran Quang De, Chang-Seon Myung, Heeyeong Cho
Journal: Acta Pharmaceutica Sinica B (2022)

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a pivotal enzyme in the Toll-like receptor (TLR)/MYD88 dependent signaling pathway, which is highly activated in rheumatoid arthritis tissues and activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of lymphoma. Moreover, proviral integration site for Moloney murine leukemia virus 1 (PIM1) functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib resistance. We developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF-κB pathway and proinflammatory cytokine induction in vitro and in vivo. In rheumatoid arthritis mouse models, treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation. KIC-0101 inhibited the nuclear translocation of NF-κB and activation of JAK/STAT pathway in ABC-DLBCLs. In addition, KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF-κB pathway and PIM1 kinase. Our results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas.
Research Opportunities in the Treatment of Mitral Valve Prolapse
Authors: Francesca N. Delling, Peter A. Noseworthy, David H. Adams, Cristina Basso, Michael Borger, Nabila Bouatia-Naji, Sammy Elmariah, Frank Evans, Edward Gerstenfeld, Judy Hung, Thierry Le Tourneau, John Lewis, Marc A. Miller, Russell A. Norris, Muralidhar Padala, Martina Perazzolo-Marra, Dipan J. Shah, Jonathan W. Weinsaft, Maurice Enriquez-Sarano, Robert A. Levine
Journal: Journal of the American College of Cardiology (2022)

In light of the adverse prognosis related to severe mitral regurgitation, heart failure, or sudden cardiac death in a subset of patients with mitral valve prolapse (MVP), identifying those at higher risk is key. For the first time in decades, researchers have the means to rapidly advance discovery in the field of MVP thanks to state-of-the-art imaging techniques, novel omics methodologies, and the potential for large-scale collaborations using web-based platforms. The National Heart, Lung, and Blood Institute recently initiated a webinar-based workshop to identify contemporary research opportunities in the treatment of MVP. This report summarizes 3 specific areas in the treatment of MVP that were the focus of the workshop: 1) improving management of degenerative mitral regurgitation and associated left ventricular systolic dysfunction; 2) preventing sudden cardiac death in MVP; and 3) understanding the mechanisms and progression of MVP through genetic studies and small and large animal models, with the potential of developing medical therapies.
Surveillance of the progression and assessment of treatment endpoints for nonalcoholic steatohepatitis
Authors: Yi-wen Shi, Jian-Gao Fan
Journal: Clinical and Molecular Hepatology (2022)

Nonalcoholic steatohepatitis (NASH) is an aggressive form of nonalcoholic fatty liver disease (NAFLD) characterized by steatosis-associated inflammation and liver injury. Without effective treatment or management, NASH can have life-threatening outcomes. Evaluation and identification of NASH patients at risk for adverse outcomes are therefore important. Key issues in screening NASH patients are the assessment of advanced fibrosis, differentiation of NASH from simple steatosis, and monitoring of dynamic changes during follow-up and treatment. Currently, NASH staging and evaluation of the effectiveness for drugs still rely on pathological diagnosis, despite sample error issues and the subjectivity associated with liver biopsy. Optimizing the pathological assessment of liver biopsy samples and developing noninvasive surrogate methods for accessible, accurate, and safe evaluation are therefore critical. Although noninvasive methods including elastography, serum soluble biomarkers, and combined models have been implemented in the last decade, noninvasive diagnostic measurements are not widely applied in clinical practice. More work remains to be done in establishing cost-effective strategies both for screening for at-risk NASH patients and identifying changes in disease severity. In this review, we summarize the current state of noninvasive methods for detecting steatosis, steatohepatitis, and fibrosis in patients with NASH, and discuss noninvasive assessments for screening at-risk patients with a focus on the characteristics that should be monitored at follow-up.
Racial/Ethnic and Sex Differences in Somatic Cancer Gene Mutations among Patients with Early-Onset Colorectal Cancer
Authors: Andreana N. Holowatyj, Wanqing Wen, Timothy Gibbs, Hannah M. Seagle, Samantha R. Keller, Digna R. Velez Edwards, Mary K. Washington, Cathy Eng, Jose Perea, Wei Zheng, Xingyi Guo
Journal: Cancer Discovery (2022)

Abstract Molecular features underlying colorectal cancer disparities remain uncharacterized. Here, we investigated somatic mutation patterns by race/ethnicity and sex among 5,856 non-Hispanic white (NHW), 535 non-Hispanic Black (NHB), and 512 Asian/Pacific Islander (API) patients with colorectal cancer (2,016 early-onset colorectal cancer patients: sequencing age &amp;lt;50 years). NHB patients with early-onset nonhypermutated colorectal cancer, but not API patients, had higher adjusted tumor mutation rates than NHW patients. There were significant differences for LRP1B, FLT4, FBXW7, RNF43, ATRX, APC, and PIK3CA mutation frequencies in early-onset nonhypermutated colorectal cancers between racial/ethnic groups. Heterogeneities by race/ethnicity were observed for the effect of APC, FLT4, and FAT1 between early-onset and late-onset nonhypermutated colorectal cancer. By sex, heterogeneity was observed for the effect of EP300, BRAF, WRN, KRAS, AXIN2, and SMAD2. Males and females with nonhypermutated colorectal cancer had different trends in EP300 mutations by age group. These findings define genomic patterns of early-onset nonhypermutated colorectal cancer by race/ethnicity and sex, which yields novel biological clues into early-onset colorectal cancer disparities. Significance: NHBs, but not APIs, with early-onset nonhypermutated colorectal cancer had higher adjusted tumor mutation rates versus NHWs. Differences for FLT4, FBXW7, RNF43, LRP1B, APC, PIK3CA, and ATRX mutation rates between racial/ethnic groups and EP300, KRAS, AXIN2, WRN, BRAF, and LRP1B mutation rates by sex were observed in tumors of young patients. See related commentary by Shen et al., p. 530 . This article is highlighted in the In This Issue feature, p. 517
Microbial vitamin production mediates dietary effects on diabetic risk
Authors: Daoming Wang, Van T. Pham, Robert E. Steinert, Alexandra Zhernakova, Jingyuan Fu
Journal: Gut Microbes (2022)

Adequate levels of essential vitamins are important for the prevention of diabetes. While the main efforts to address this are currently focused on the intake of vitamin supplements, improving and maintaining intrinsic vitamin production capacity, which is determined by gut microbes, has received insufficient attention. In this study, we systematically investigated the relationship between gut microbial vitamin production and factors related to diabetes and cardiometabolic health in a deeply phenotyped cohort, Lifelines-DEEP (N = 1,135). We found that blood glucose–related factors, lipids, circulating inflammation, and fecal short-chain fatty acids are associated with gut microbial vitamin production. Use of laxatives and metformin are associated with increased levels of vitamin B1/B6 biosynthesis pathways. We further reveal a mediatory role for microbial vitamin B1/B2 production on the influence of fruit intake on diabetes risk. This study provides preliminary evidence for microbiome-targeted vitamin metabolism interventions to promote health.
CRAG: de novo characterization of cell-free DNA fragmentation hotspots in plasma whole-genome sequencing
Authors: Xionghui Zhou, Haizi Zheng, Hailu Fu, Kelsey L. Dillehay McKillip, Susan M. Pinney, Yaping Liu
Journal: Genome Medicine (2022)

Abstract The fine-scale cell-free DNA fragmentation patterns in early-stage cancers are poorly understood. We developed a de novo approach to characterize the cell-free DNA fragmentation hotspots from plasma whole-genome sequencing. Hotspots are enriched in open chromatin regions, and, interestingly, 3′end of transposons. Hotspots showed global hypo-fragmentation in early-stage liver cancers and are associated with genes involved in the initiation of hepatocellular carcinoma and associated with cancer stem cells. The hotspots varied across multiple early-stage cancers and demonstrated high performance for the diagnosis and identification of tissue-of-origin in early-stage cancers. We further validated the performance with a small number of independent case–control-matched early-stage cancer samples.
NAD precursors cycle between host tissues and the gut microbiome
Authors: Karthikeyani Chellappa, Melanie R. McReynolds, Wenyun Lu, Xianfeng Zeng, Mikhail Makarov, Faisal Hayat, Sarmistha Mukherjee, Yashaswini R. Bhat, Siddharth R. Lingala, Rafaella T. Shima, Hélène C. Descamps, Timothy Cox, Lixin Ji, Connor Jankowski, Qingwei Chu, Shawn M. Davidson, Christoph A. Thaiss, Marie E. Migaud, Joshua D. Rabinowitz, Joseph A. Baur
Journal: Cell Metabolism (2022)
A randomized controlled trial showing safety and efficacy of a whole sporozoite vaccine against endemic malaria
Authors: Sodiomon B. Sirima, Alphonse Ouédraogo, Alfred B. Tiono, Jean M. Kaboré, Edith C. Bougouma, Maurice S. Ouattara, Désiré Kargougou, Amidou Diarra, Noelie Henry, Issa N. Ouédraogo, Peter F. Billingsley, Anita Manoj, Yonas Abebe, Natasha KC, Adam Ruben, Thomas L. Richie, Eric R. James, Sudhaunshu Joshi, Biraj Shrestha, Kathy Strauss, Kirsten E. Lyke, Christopher V. Plowe, Gail E. Potter, Catherine Cox, Walter Jones, B. Kim Lee Sim, Stephen L. Hoffman, Matthew B. Laurens
Journal: Science Translational Medicine (2022)

A highly effective malaria vaccine remains elusive despite decades of research. Plasmodium falciparum sporozoite vaccine (PfSPZ Vaccine), a metabolically active, nonreplicating, whole parasite vaccine demonstrated safety and vaccine efficacy (VE) against endemic P. falciparum for 6 months in Malian adults receiving a five-dose regimen. Safety, immunogenicity, and VE of a three-dose regimen were assessed in adults in Balonghin, Burkina Faso in a two-component study: an open-label dose escalation trial with 32 participants followed by a double-blind, randomized, placebo-controlled trial (RCT) with 80 participants randomized to receive three doses of 2.7 × 106 PfSPZ (N = 39) or normal saline (N = 41) just before malaria season. To clear parasitemia, artesunate monotherapy was administered before first and last vaccinations. Thick blood smear microscopy was performed on samples collected during illness and every 4 weeks for 72 weeks after last vaccinations, including two 6-month malaria transmission seasons. Safety outcomes were assessed in all 80 participants who received at least one dose and VE for 79 participants who received three vaccinations. Myalgia was the only symptom that differed between groups. VE (1 - risk ratio; primary VE endpoint) was 38% at 6 months (P = 0.017) and 15% at 18 months (0.078). VE (1 - hazard ratio) was 48% and 46% at 6 and 18 months (P = 0.061 and 0.018). Two weeks after the last dose, antibodies to P. falciparum circumsporozoite protein and PfSPZ were higher in protected versus unprotected vaccinees. A three-dose regimen of PfSPZ Vaccine demonstrated safety and efficacy against malaria infection in malaria-experienced adults.
CSF-to-dura gateways
Authors: Jean-Leon Thomas, Helene Benveniste
Journal: The Journal of Experimental Medicine (2022)

Postmortem microstructural studies together with in vivo magnetic resonance imaging show that human arachnoid granulations are porous channels that serve as transient filtration conduits for cerebrospinal fluid to flow directly into dural interstitial tissue, but not into venous sinuses (Shah et al. 2022. J. Exp. Med.https://doi.org/10.1084/jem.20220618).
Distance-dependent inhibition of translation initiation by downstream out-of-frame AUGs is consistent with a Brownian ratchet process of ribosome scanning
Authors: Ke Li, Jinhui Kong, Shuo Zhang, Tong Zhao, Wenfeng Qian
Journal: Genome biology (2022)

Eukaryotic ribosomes are widely presumed to scan mRNA for the AUG codon to initiate translation in a strictly 5'-3' movement (i.e., strictly unidirectional scanning model), so that ribosomes initiate translation exclusively at the 5' proximal AUG codon (i.e., the first-AUG rule).
Peri‐procedural management of transcatheter mitral valve replacement in patients with heart failure
Authors: Sara L. Hungerford, Gry Dahle, Alison Duncan, Christopher S. Hayward, David W.M. Muller
Journal: European Journal of Heart Failure (2022)

Over the past decade, transcatheter mitral valve replacement (TMVR) technologies have evolved with the objective of improving outcomes for patients with severe mitral regurgitation (MR) deemed unsuitable for conventional mitral valve surgery. Although the safety and efficacy of transcatheter edge‐to‐edge mitral valve repair (TEER) is well‐established, there is a sense amongst innovators that a major advantage of TMVR may be to offer a more complete solution for the correction of MR in patients whose complex anatomy means that the likelihood of achieving grade 0 or 1 MR with TEER is low. However, abrupt correction of MR in a poorly prepared left ventricle poses a number of unique haemodynamic challenges, particularly when sudden elimination of regurgitant flow causes a relative increase in left ventricular (LV) afterload. Rapid reduction in LV cavity size following MR elimination may itself result in relative LV outflow tract obstruction (LVOTO), irrespective of the intrinsic risk of LVOTO associated with TMVR. Nevertheless, TMVR on a beating heart affords the opportunity to study real‐time invasive cardiac indices in high‐risk patients with acute reversal of severe MR.
Targeting Nitric Oxide: Say NO to Metastasis
Authors: Tejaswini P. Reddy, Sharon A. Glynn, Timothy R. Billiar, David A. Wink, Jenny C. Chang
Journal: Clinical Cancer Research (2022)

Abstract Utilizing targeted therapies capable of reducing cancer metastasis, targeting chemoresistant and self-renewing cancer stem cells, and augmenting the efficacy of systemic chemo/radiotherapies is vital to minimize cancer-associated mortality. Targeting nitric oxide synthase (NOS), a protein within the tumor microenvironment, has gained interest as a promising therapeutic strategy to reduce metastatic capacity and augment the efficacy of chemo/radiotherapies in various solid malignancies. Our review highlights the influence of nitric oxide (NO) in tumor progression and cancer metastasis, as well as promising preclinical studies that evaluated NOS inhibitors as anticancer therapies. Lastly, we highlight the prospects and outstanding challenges of using NOS inhibitors in the clinical setting.
Health-related quality of life by race, ethnicity, and country of origin among cancer survivors
Authors: Bryce B Reeve, Kristi D Graves, Li Lin, Arnold L Potosky, Jaeil Ahn, Debra M Henke, Wei Pan, Jane M Fall-Dickson
Journal: JNCI Journal of the National Cancer Institute (2022)

Typical cancer research studies of health-related quality of life (HRQOL) in the United States do not include country of origin when examining race and ethnic group differences. This population-based, cross-sectional study used an innovative methodology to examine how self-reported racial and ethnic groups, by country of origin, report differential HRQOL experiences after adjusting for clinical and demographic characteristics, including socioeconomic status.Recruited from 4 cancer registries in California, Louisiana, and New Jersey, cancer survivors completed Patient-Reported Outcomes Measurement Information System measures of fatigue, pain interference, anxiety, depression, sleep disturbance, physical function, ability to participate in social roles, and cognitive function. Latent profile analysis clustered survivors in HRQOL clusters based on including all the Patient-Reported Outcomes Measurement Information System domains.The 5366 participants (60% female; 40% male; average age of 59.8 years) included 17% Asian, 18% Black, 21% Hispanic, and 41% White survivors. Survivors were grouped into 4 clusters: high HRQOL (26%), average HRQOL (34%), low HRQOL (29%), and very low HRQOL (11%). Among many differences by race, ethnicity, and country of origin, Caribbean cancer survivors were more likely to be in the very low HRQOL cluster (odds ratio = 2.67, 95% confidence interval = 1.31 to 5.43) compared with non-Hispanic White survivors. Similarly, American Indian and Alaska Native, Cuban, Dominican, and Puerto Rican cancer survivors had relatively high percentages in the very low HRQOL cluster.This study found statistically significant differences in HRQOL experience by race, ethnicity, and country of origin, even after adjusting for social determinants of health. These findings inform future HRQOL research to include these self-reported factors.